Antisense Oligonucleotide Inhibition of Apolipoprotein C-III Reduces Plasma Triglycerides in Rodents, Nonhuman Primates, and Humans

Abstract

Rationale: Elevated plasma triglyceride levels have been recognized as a risk factor for the development of coronary heart disease. Apolipoprotein C-III (apoC-III) represents both an independent risk factor and a key regulatory factor of plasma triglyceride concentrations. Furthermore, elevated apoC-III levels have been associated with metabolic syndrome and type 2 diabetes mellitus. To date, no selective apoC-III therapeutic agent has been evaluated in the clinic. Objective: To test the hypothesis that selective inhibition of apoC-III with antisense drugs in preclinical models and in healthy volunteers would reduce plasma apoC-III and triglyceride levels. Methods and Results: Rodent- and human-specific second-generation antisense oligonucleotides were identified and evaluated in preclinical models, including rats, mice, human apoC-III transgenic mice, and nonhuman primates. We demonstrated the selective reduction of both apoC-III and triglyceride in all preclinical pharmacological evaluations. We also showed that inhibition of apoC-III was well tolerated and not associated with increased liver triglyceride deposition or hepatotoxicity. A double-blind, placebo-controlled, phase I clinical study was performed in healthy subjects. Administration of the human apoC-III antisense drug resulted in dose-dependent reductions in plasma apoC-III, concomitant lowering of triglyceride levels, and produced no clinically meaningful signals in the safety evaluations. Conclusions: Antisense inhibition of apoC-III in preclinical models and in a phase I clinical trial with healthy subjects produced potent, selective reductions in plasma apoC-III and triglyceride, 2 known risk factors for cardiovascular disease. This compelling pharmacological profile supports further clinical investigations in hypertriglyceridemic subjects.

Remnant Lipoprotein Cholesterol and Incident Coronary Heart Disease: The Jackson Heart and Framingham Offspring Cohort Studies

“…apoCIII is an integral component of RLPs and inhibits the function of lipoprotein lipase and hepatic lipase, while potentially promoting VLDL assembly 44, 45. Development of an antisense oligonucleotide inhibitor of apoCIII is under way, and phase 3 studies are anticipated 46. Our findings suggest targeting participants with elevated RLP‐C in such studies, as RLP‐C levels are likely a more specific measure of RLP burden compared with less specific surrogates such as TGs, which were not predictive in this population.…”

Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol

“…Carriers of rare loss-offunction mutations in the APOC3 gene have low TG levels and reduced CVD risk (95,96). Antisense inhibition of apoC3 in preclinical models and in a phase I clinical trial of healthy subjects decreased plasma concentrations of apoC3 and TG (97). In three patients with familial chylomicronemia syndrome, APOC3 antisense RNA dramatically reduced TG levels and decreased the numbers of chylomicron and VLDL particles (58).…”

Antisense-Mediated Lowering of Plasma Apolipoprotein C-III by Volanesorsen Improves Dyslipidemia and Insulin Sensitivity in Type 2 Diabetes

“…Potent second-generation antisense oligonucleotides (ASOs) have been developed to reduce apoC-III expression in animals and humans (18). In mice, administration of a species-specific apoC-III ASO led to dose-dependent reductions in hepatic apoC-III mRNA and plasma apoC-III protein.…”

“…In dyslipidemic rodent models, this led to .50% reductions in both fasting and postprandial plasma TG. Recapitulating preclinical models, treating normolipidemic and hypertriglyceridemic human subjects with the human-specific apoC-III ASO, volanesorsen (ISIS 304801), profoundly reduced plasma apoC-III protein and plasma TG levels (18,19). This included subjects with familial chylomicronemia syndrome (FCS), who have extreme hypertriglyceridemia due to loss-offunction mutations leading to absent LPL activity (20).…”